Excitatory amino acids (glutamic acid, aspartic acid, etc.) play important roles as neurotransmitters in mammals. On the other hand, there have been reported findings one after another that abnormal excitation of excitatory amino acid receptors is one of the causative factors of nerve cell death occurring in brain ischemia, head injury, Alzheimer's disease, Parkinson's disease, Huntington's chorea, etc. It is also suggested that abnormalities in these excitatory amino acid receptors participate in the onset of schizophrenia. Under these circumstances, studies have been vigorously made on excitatory amino acid receptor antagonists and agonists.
Regarding substances with antagonism to excitatory amino acid receptors with microbial origin, it is reported that a substance ES-242 is produced by Verticillium sp. ES-242 (J. Antibiotics, vol. 45, 88-93 (1992)).
To develop an antagonist to excitatory amino acid receptors, the present inventors have studied and searched to find a substance originating in a microbial product which is capable of inhibiting the toxicity of kainic acid on brain nerve cells.
It is also reported that kainic acid is toxic to primarily cultured chick telencephalon nerve cells and this toxicity by the excitatory amino acid is expressed via the cystine transporter system and non-N-methyl-D-aspartic acid (NMDA) receptor (Neuroscience Letters, vol. 139, 205-208 (1992)). This toxicity is inhibited by non-NMDA receptor antagonists including 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione (NBQX).
Accordingly, the present invention aims at providing a substance which is capable of inhibiting the toxicity of kainic acid on brain nerve cells and therefore useful as a remedy and a preventive for diseases caused by nervous disturbances.